Clinical Study On The Effect Of Central Sympathetic Nervous State On Ejaculation And Animal Experiment

Part One:The overactivity of the sympathetic nervous system in primary premature ejaculation Chapter I:Sympathetic skin response in patients with primary premature ejaculationBackground:Until now, the precise pathological mechanisms of primary premature ejaculation (PPE) have not been well evaluated. Recently, it has been suggested that the etiology of PPE may be somatic disorders and/or neurobiological disturbances.Objective:To evaluate the possible role of the autonomic (sympathetic) nervous system function among the PPE patients by applying neurophysiological techniques.Method:We performed sympathetic skin response located in penis (PSSR) tests in 52 patients with PPE and 46 normally potent men. The latencies and amplitudes of PSSR were measured.Results:The PSSR waveforms were classified into P type and N type according to the waveform characteristics. Of 46 normally potent subjects,18 had the P waveform types; the other 28 had the N waveform types. Among the 52 PPE patients,23 and 29 had the P and N waveform types, respectively. The waveform distribution in the PPE patients was not remarkably different from that in the control group (χ2=0.261, P= 0.609). The median (interquartile range) values of the amplitude for the PPE patients group and control group were 157.5 (120.0-322.5) and 69.5 (43.0-112.5) mV, respectively, the former being significantly larger than the latter (P<0.001). The mean latency values of the two groups were 1272.9±149.8 and 1514.5±168.3 ms, respectively; in other words, the mean latency of PSSR in the patients with PPE was 241.6 ms shorter than that in the control group, and the difference was statistically evident between them (P<0.001). Logistic regression analysis was further performed to investigate the independent impact of PSSR (latencies and amplitudes) on PPE, controlling for the possible confounding factors, including age, height and body weight. The results demonstrated that the latencies and amplitudes of PSSR were associated with PPE (P<0.001 and P=0.002, respectively).Conclusions:Patients with PPE have hyperactivity of the sympathetic nervous system, which may be another factor involved in the pathological mechanisms of PPE, and the PSSR is an objective test to evaluate patients with PPE.Chapter II:The sympathetic skin response located in the penis as a predictor of the response to Sertraline treatment in patients with primary premature ejaculationBackground:The pathologic mechanisms of primary premature ejaculation (PPE) are complex and multifactorial, and hyperactivity of the sympathetic nervous system is one of the mechanisms. Sympathetic skin response located in the penis (PSSR) is a noninvasive biological marker of sympathetic system function.Objective:To examine the effects of sertraline on sympathetic nervous system activity and assess the predictive value of the PSSR on the response to sertraline treatment in PPE patients.Methods:Sixty-one patients with PPE were recruited. Each received 50 mg sertraline daily for 8 weeks. Before and after the experiment, the patients were evaluated for PSSR tests, and sexual performance parameters including the intravaginal ejaculation latency time (IELT) and the Chinese premature ejaculation index-5 (CIPE-5) and International Index of Erectile Function-5 (IIEF-5), were collected through a questionnaire survey and analyzed. In addition, based on the latency of PSSR, we divided the patients into a normal PSSR group and an abnormal PSSR group, and compared the sertaline treatment efficay between the two groups.Results:Overall, fifty-eight (95.1%) patients completed the entire study and were analyzed. After an 8-week setraline treatment, the IELTs of the patients were significantly prolonged; the ratio of the mean IELT to baseline showed an 8.1±6.9 fold increase, which was statistically significant compared with that before the treatment (P< 0.001). CIPE-5 score were significantly increased (P< 0.001), and the amplitudes (130.0 vs.200.0 μV, P< 0.001) and latencies (1430.4 vs.1241.0 ms, P< 0.001) of PSSR in the PPE patients were remarkably decreased and prolonged, respectively. Compared with the patients with normal baseline PSSR, those with abnormal baseline PSSR had better outcomes after sertaline treatment (χ2=7.754, P =0.021). In addition, the changes of the latencies of PSSR were positively correlated with the increment of IELT (r=0.375, P=0.004). The treatment outcome was better in patients with a baseline abnormal PSSR than in those with a baseline normal PSSR (P=0.021).Conclusions:These results suggest that clinical improvement in response to sertraline in the PPE patients, at least in part, is mediated through reducing sympathetic nervous system activity indexed by PSSR. Measurement of the PSSR appears to provide useful information for predicting treatment responses in the PPE patients. Further more, this study indicated that overactivity of sympathetic system is one particular subtypes of PPE.Part Two:NMD A receptors in hypothalamic para ventricular nucleus involved in ejaculation behavior through modulating the sympathetic nervous system Chapter I:NMD A receptors in para ventricular nucleus regulate sympathetic outflow in ratsBackground:Paraventricular nucleus of hypothalamus (PVN) is an important integrative site in regulating sympathetic outflow. The messengers of PVN involved in mediating the sympathetic outflow are mainly divided into excitatory and inhibitory neurotransmitters, which influence the function of the neurons. Objective:To estimate the role of NMD A receptors in PVN on regulating the sympathetic nervous system outflow and their time-and dose-dependent manner.Methods:Forty SD rats were randomly divided into four groups:saline and three different doses of NMD A (0.02 nmol,0.20 nmol, and 2.00 nmol) group (each n=10). Lumbar sympathetic nerve activities (LSNA) were recorded, with a four channel AC/DC differential amplifier. After bilateral PVN microinjection of saline or 0.20 nmol NMDA, the quantitative changes of norepinephrine (NE) in plasma were measured with ELISA. In addition, we also observed the effects of the saline or AP-5 pretreatment on the LSNA changes due to the bilateral PVN microinjection of 0.20 nmol NMDA.Result:Bilateral PVN microinjection of NMDA (0.02 nmol,0.20 nmol, and 2.0 nmol) significantly enhanced the activities of LSNA in a dose-dependent manner, which expressed a definite linear correlation (r=0.875, P=0.04). In addition, the more dose of NMDA, the longer its effects last. After bilateral PVN microinjection of saline or 0.20 nmol NMDA, the NE levels were respectively 1453.4±136.4 pg/ml and 492.3±36.8 pg/ml, compared with the baseline, the NE levels of both groups are considerably increased (P=0.001). However, the increment of 0.20 nmol NMDA group was more remarkable. At the same time, the pretreatment AP5 could prevent or remove the enhanced LSNA changes due to the bilateral PVN microinjection of 0.20 nmol NMDA.Conclusions:From the aspects of LSNA and periphery NE level, we demonstrated that the NMDA receptors in PVN are involved in the mediation of the sympathetic nervous system outflow.Chapter Ⅱ:Regulation of NMD A receptors in para ventricular nucleus and its effects on the male ejaculation behavior in the ratBackground:The neurons related to the sexual behavior are extensively distributed in the olfactory bulb, hypothalamus, hippocampus and amygdale. One of the most important areas is PVN, which has been proved to regulate the sympathetic nervous system outflow through NMDA receptors.Objective:To assess the effects of NMDA receptors in PVN on the male sexual behavior, specifically ejaculation.Methods:Thirty male SD rats copulated with the receptive females, and the ones with the ejaculation capability were selected. The selected rats were implanted with stainless steel guide cannulas above the PVN, each with microinjection of NMDA (2.0 nmol), saline and AP-5 (10.0 nmol) in counterbalanced order. Behavioral testing occurred once a week. Copulatory behaviors experiment was started approximately 5 minutes after the microinjection, and the following measures were recorded:mount latency, intromission latency, ejaculation latency, post-ejaculation interval, mount frequency, intromission frequency, intromission ratio and ejaculation frequency.Results:Totally,16 rats had the correct implanted cannulas above the PVN and were included for further analysis. No changes in mount latency were observed after NMDA or AP-5 microinjection (P=0.423). However, microinjection of NMDA increased the intromission ratio (P=0.042); additionally, it not only significantly reduced the mount and intromission frequency (P< 0.001, P=0.003), but also shortened the latency of intromission and ejaculation (P=0.001, P<0.001). On the contrary, AP-5 increased the frequency of the mount and intromission (P<0.001, both), and prolonged the latency of intromission and ejaculation (both P<0.001), resulting in decreasing the intromission ratio (P=0.048). In addition, compared with the saline, NMDA and AP-5 respectively increased and reduced the ejaculation frequency during the 30 min sexual behavior experiment; at the same time, they respectively and relatively shortened and prolonged the postejaculation interval (all P <0.001).Conclusions:NMD A receptors in PVN are involved in the regulation of the male rat’s erectile function, and they also play important roles in ejaculation function.Charpter III:Sympathetic nervous system and the expression of NMDA receptors in PVN of different ejaculators in male ratsBackground:PVN is not only an important central site for the integration of sympathetic nerve activity, but also plays an important role in ejaculation function. In our previous study, we found that the mediation of sympathetic nervous system through NMDA receptors in PVN could affect the ejaculation behavior in male rats.Objective:To elucidate whether variations in ejaculation latencies in an experimental rat model for ejaculation behaviors are linked to differences of sympathetic nervous system and the expression of NMD A receptors in PVN.Methods:Forty-nine rats received six training sessions and the last three results obtained during these sessions were used to divide the rats into different groups of sexual performance. The rats were matched into sluggish, normal and rapid ejaculators on the basis of their average ranking score on EF. The LSNA (baseline and sensitivity) activity and plasma NE were measured and recorded. In addition, NMDA receptors expression was analyzed with immunohistochemistry and Western blot.Results:Thirty-three rats were included for analysis, and their EF scores were normally distributed. The plasma NE of "sluggish", "normal", and "rapid" ejaculating rats were respectively 757.8±421.4 pg/ml,1429.0±675.5 pg/ml, and 1674.4±651.5 pg/ml, which showed significant difference (F=4.226, P=0.03). The baseline LSNA activities of the three groups were 1463.3±476.4 mV·s,1662.3±601.2 mV·s, and 1683.4±491.3 mV·s, respectively, showing no statistical difference (F=0.355, P= 0.706). However, the sensitivity of LSNA between the three groups showed significant differences, with 28.9±8.1%,48.4±7.5%, and 88.7±7.4%(F=63.1, P < 0.001). In addition, the expression of NMDA receptors in PVN of the three groups were significantly different (F=15.054, P=0.005), with the most rich in "rapid" ejaculating rats, then less in the "normal" ones, and the least in the "sluggish" ones. Furthermore, the expression of NMDA receptors are positively correlated with the sensitivity of LSNA (r=0.876, P=0.022).Conclusions:we provide the first scientific evidence supporting a neurophysiological (sensitivity of sympathetic system nervous) difference between"rapid," "normal," and "sluggish" ejaculators, and the sensitivities are positively correlated with the NMDA receptors expression. The results further demonstrate that the increased NMDA receptors in PVN lead to the hyperactivity of sympathetic system nervous, which results in premature ejaculation.